Autoimmunity Reviews 12 (2013) 410–415

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Autoimmunity Reviews
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Review

Pulmonary hypertension in systemic lupus erythematosus: prevalence, predictors

and diagnostic strategy
Guillermo Ruiz-Irastorza ⁎, Maider Garmendia, Irama Villar, Maria-Victoria Egurbide, Ciriaco Aguirre
Autoimmune Diseases Research Unit, Department of Internal Medicine, Hospital Universitario Cruces, University of the Basque Country, UPV/EHU, Bizkaia, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: To investigate the prevalence and predictors of pulmonary hypertension (PH) in patients with
Received 2 July 2012 systemic lupus erythematosus (SLE) and to validate a diagnostic strategy.
Accepted 18 July 2012 Methods: 245 patients with SLE entered a screening program. Possible PH was defined as two consecutive
Available online 25 July 2012 systolic pulmonary arterial pressure (PAP) values ≥ 40 mm Hg by echocardiography. The subsequent
diagnostic procedure, including right heart catheterization if needed, confirmed or excluded the diagnosis
Keywords:
of PH secondary to cardiopulmonary disease or SLE-related pulmonary arterial hypertension (PAH). Independent
Pulmonary arterial hypertension
Damage
predictors of PH were identified by multivariant multiple linear or logistic regression models. The sensitivity (S),
Lupus activity specificity (SP), positive (PPV) and negative predictive values (NPV) were calculated for different screening cutoff
Antiphospholipid values.
Anti-RNP Results: 88% patients were women. The mean (SD) age at the time of enrolment was 45 (16) years. 12 cases of PH
Raynaud's were detected, all secondary, with a resulting prevalence of 5%. Two consecutive echocardiographic PAP
measurements≥40 mm Hg performed best as the cutoff point for screening (S 100%, SP 97%, PPV 70, NPV 100),
as compared with single PAP measurements≥30 mm Hg or ≥40 mm Hg The age at the time of enrolment
was the only variable independently associated with PAP values (p=0.0001), with the SLICC damage index
score showing a borderline association (p=0.08). Only the age at the time of enrolment showed an independent
association with PH (OR 1.10, 95% CI 1.06–1.17).
Conclusion: We found a low prevalence of PH. Screening echocardiograms in asymptomatic lupus patients are thus
not recommended. Two consecutive PAP values≥40 mm Hg by echocardiogram is the best screening cutoff for
starting investigations in SLE patients with suspected PH.
© 2012 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
2.1. Study design and objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
2.2. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
2.3. Pulmonary hypertension screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
2.4. Working definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
2.5. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
2.6. Literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
3.1. Clinical characteristics of the cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
3.2. Prevalence of PH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
3.3. Sensitivity, specificity and predictive values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
3.4. Clinical associations of estimated PAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
3.5. Clinical associations of PH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413

Abbreviations: SLE, systemic lupus erythematosus; PAP, pulmonary arterial pressure; mPAP, mean pulmonary arterial pressure; TJV, tricuspid jet velocity; RVSP, right ventricular
systolic pressure; PAD, right atrial pressure; PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; SD, standard deviation; S, sensitivity; SP, specificity; PPV, positive
predictive value; NPV, negative predictive value; SDI, systemic lupus international collaborating clinics damage index; SLEDA, systemic lupus erythematosus disease activity index.
⁎ Corresponding author at: Servicio de Medicina Interna, Hospital de Cruces, 48903-Bizkaia, Spain. Tel.: +34 94 600 63 48; fax: +34 94 600 66 17.
E-mail address: r.irastorza@euskaltel.net (G. Ruiz-Irastorza).

1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2012.07.010
 G. Ruiz-Irastorza et al. / Autoimmunity Reviews 12 (2013) 410–415 411

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
Contributorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
.
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
.

1. Introduction A screening program for detecting PH was carried out between

Pulmonary hypertension (PH) is characterized by the progressive
increase in pulmonary vascular resistance, eventually leading to right
ventricular failure. It is defined as a resting mean pulmonary arterial
pressure (mPAP)≥25 mm Hg measured by right heart catheterization.
For the diagnosis of the subclass known as pulmonary arterial hyperten-
sion (PAH), a measured pulmonary arterial wedge pressureb 15 mm Hg
is required [1,2]. Transthoracic Doppler echocardiography is the most
widely used screening test for PH in the presence of clinical suspicion
and/or predisposing conditions [2], despite the fact that echocardiogra-
phy can miss asymptomatic patients with early mild PH [3]. Right heart
catheterization is considered the definitive diagnostic method [2,3].
The clinical classification of PH was last updated in 2008 [3], with PAH
associated with systemic autoimmune diseases being included within the
Group I. Indeed, PAH is a recognized complication of systemic sclerosis,
and, much less frequently, systemic lupus erythematosus (SLE) [4,5]. In
addition, PH in SLE can be secondary to chronic thromboembolic disease
or cardiopulmonary complications [3,5].
PH has been identified as a predictor of morbidity and mortality in
SLE [6,7]. Several variables have been proposed as potential risk factors
for PH: Raynaud's phenomenon [6,8–10], antiphospholipid antibodies
[11,12], antiU1-RNP antibodies [8,13] and disease activity [8,14]. The
prevalence of PH is variable across the different lupus cohorts, ranging
from less than 2% [15] to 43% [16]. Such discordant results may actually
reflect the varying definitions of PH and the differences in the diagnostic
protocols. In fact, there are no standardized guidelines for the screening
of PH in SLE.
2. Methods
2.1. Study design and objectives
October 2004 and December 2009. The 245 lupus patients on active
follow up entered the screening program, irrespective of the presence
of dyspnea.
2.3. Pulmonary hypertension screening
A Philips SONOS 7500 echocardiography, 3-MHz probe, including
two-dimensional anatomical image, M mode echocardiography
and Doppler was used for this study. All the studies were performed
by the same two cardiologists specialized in echocardiography. An
estimation of the pulmonary artery systolic pressure (PAP), equivalent
to the right ventricular systolic pressure (RVSP) in the absence of
obstruction of pulmonary outflow tract, was calculated using the mod-
ified Bernoulli equation: RVSP = 4v2 + PAD, where v is the measured
tricuspid jet velocity (TJV), and PAD is the estimated right atrial pres-
sure, predetermined at 5 mm Hg. According to recent international
guidelines, an estimated PAP value≥40 mm Hg was considered the
suggestive limit for PH [2].
At least one transthoracic echocardiography was performed
to each patient. According to the study protocol, all patients with a
PAP ≥ 40 mm Hg had a second echocardiogram done within a period
of 6 months to 1 year. Additional echocardiograms were performed
in the remaining patients at the discretion of the attending physician.
Patients with two serial estimated PAP ≥ 40 mm Hg were consid-
ered candidates for further study. The subsequent diagnostic process
included, depending on the clinical situation and TJV measured in the
echocardiograms, additional echocardiograms and clinical observa-
tion, pulmonary function tests, chest computed tomography, ventila-
tion/perfusion lung scan, 6-minutes walking test and, eventually, a
right heart catheterization in order to establish the definitive diagno-
sis of secondary PH or SLE-related PAH.

2.4. Working definitions

This cross-sectional study has the main objective of establishing
the prevalence of PH and PAH in an observational longitudinal cohort
of SLE patients. The secondary objectives were to identify potential
predictors for PH and to validate a screening program to detect PH
in lupus patients.
2.2. Patients
The Lupus-Cruces cohort is a longitudinal observational cohort joining
SLE patients fulfilling the 1997 classification criteria of the American
College of Rheumatology [17]. At enrolment, all patients signed an
informed consent authorizing the use of their clinical data for epide-
miological studies. The local institutional review board approved the
Lupus-Cruces cohort study and the informed consent form.
At each follow-up visit, different variables are collected in a database:
demographic characteristics (age, sex, race, year of diagnosis, death and
cause of death) manifestations of SLE (clinical, target organ involvement),
autoantibody profile (anti DNA, anti-Ro, anti-La, anti-RNP, anti-Sm,
antiphospholipid), treatment received (glucocorticoids, immunosup-
pressives, antimalarials, anticoagulants…) and complications of the dis-
ease and/or treatment (infections, renal transplantation, osteoporosis,
diabetes, retinopathy, cancer). The systemic lupus international collabo-
rating clinics (SLICC) damage index (SDI) [18] is calculated yearly. The
systemic lupus erythematosus disease activity index (SLEDAI) [19] was
calculated in retrospect.
Possible PH was defined as two consecutive echocardiograms with
PAP ≥ 40 mm Hg.
Secondary PH was diagnosed in patients with possible PH plus one
of the following conditions: cardiomyopathy with systolic or diastolic
dysfunction, moderate-severe valvular dysfunction, restrictive lung dis-
ease, chronic pulmonary thromboembolism or severe chronic obstructive
pulmonary disease [3]. Patients with a right heart catheterization show-
ing a resting mPAP≥25 mm Hg and a measured pulmonary arterial
wedge pressure≥15 mm Hg were also diagnosed of secondary PH [2,3].
SLE-induced PAH was diagnosed in the presence of a resting
mPAP≥25 mm Hg plus pulmonary arterial wedge pressureb 15 mm Hg
measured by right heart catheterization [2,3].
2.5. Statistical analysis
The clinical descriptors of our cohort were generated, using means
with standard deviation (SD) or proportions, as indicated. The prevalence
of possible PH and definite PH, both secondary and SLE-associated PAH,
was calculated. In order to identify the possible predictors of PAP values,
PH and PAH, the following strategy was followed: univariate linear
regression was performed on each possible predictor of the first PAP
value. Likewise, univariate conditional logistic regression was performed
on each of the same independent variables to test their association with
PH. The same analysis would be performed with PAH as the dependent
412 G. Ruiz-Irastorza et al. / Autoimmunity Reviews 12 (2013) 410–415

variable, if any cases were detected. The following independent variables Table 1
were tested against each dependent variable: age at SLE diagnosis, age Clinical characteristics of the cohort.

at the time of the echocardiogram, disease duration, sex, past history Age at SLE diagnosis (years) 34 (15)
of lupus nephritis, pleuropulmonary lupus disease (including pleuritis, Mean (SD)
interstitial lung disease and shrinking lung syndrome), thrombosis, Age at enrolment 45 (16)
Mean (SD)
antiphospholipid syndrome, presence of Raynaud's phenomenon, arterial
Female 217/245 (89%)
hypertension, smoking (current or past), anti DNA, anti-Ro, anti-La, Race:
anti-U1RNP and antiphospholipid antibodies, past treatment received Caucasian 243/245 (99.2%)
with hydroxychloroquine, prednisone, cyclophosphamide, azathioprine, Afro-Caribbean 2/245 (0.8%)
Cumulative SLE clinical manifestations:
methotrexate and mycophenolate mofetil, SDI and SLEDAI scores at the
Rash 160/245 (65%)
time of the first echocardiogram. Those variables with a p value≤0.1 Livedo 28/245 (11%)
in the univariate analysis were subsequently included in multivariant Arthritis 146/245 (60%)
multiple linear or logistic regression models, as indicated according to Lupus nephritis 56/245 (23%)
the dependent continuous or dichotomic variable (PAP value, PH, PAH), Thrombosis 48/245 (20%)
Antiphospholipid syndrome 38/245 (15%)
in order to identify independent associations.
Raynaud's phenomenon 92/245 (37%)
To assess the association between SLE activity and PAP values, a Pleuropulmonary disease 22/245 (9%)
univariate linear regression was performed using the variables PAP Autoantibodies:
variation (estimated PAP value in echocardiogram 2–estimated PAP ANAs 240/245 (98%)
value in echocardiogram 1) and SLEDAI variation (SLEDAI 2–SLEDAI 1). Anti DNA 169/245 (69%)
Anti Ro/SS-A 88/245 (36%)
Finally, the sensitivity, specificity, positive and negative predictive Anti La/SS-B 40/245 (16%)
values were calculated for the different possible echocardiographic Anti RNP 56/245 (23%)
cutoff values (i.e., one PAP ≥ 30 mm Hg, one PAP ≥ 40 mm Hg or Anti-Sm 46/245 (19%)
two consecutive PAP ≥ 40 mm Hg) in the detection of PH. Given the Antiphospholipid 99/245 (40%)
Cumulative treatments:
ethical and practical impossibility of performing a diagnostic right
Prednisone 217/245 (89%)
heart catheterization to all participants, our final diagnosis after com- Hydroxychloroquine 209/245 (85%)
pleting the study (PH yes/no) was considered the gold standard. Cyclophosphamide 63/245 (26%)
All calculations were done using the STATA 11.1 statistical package Azathioprine 87/245 (35%)
(StataCorp, Tx, USA). Methotrexate 49/245 (20%)
Mycophenolate mofetil 30/245 (12%)
Cyclosporine 13/245 (5%)
2.6. Literature review Others:
Smoking 108/245 (44%)
A MEDLINE search was performed using the terms “systemic lupus Hypertension 90/245 (36%)
erythematosus” and “pulmonary hypertension”. We selected for litera-
ture review cohort studies in which the prevalence and/or predictors of
PH were reported.
A second echocardiogram was thus performed to 31 patients with an
3. Results initial PAP≥40 mm Hg. In this subgroup, the mean PAP (SD) declined
from 44.8 mm Hg (5.6) in the first echocardiogram to 40.7 mm Hg
3.1. Clinical characteristics of the cohort (10.3) in the second (mean difference −4.1, 95% CI 0.6–7.4, p=0.02).
Seventeen patients (54%, 7% of the whole cohort) had a PAP≥40 mm Hg
Two hundred forty five patients were included in the study in the second echocardiogram, being thus diagnosed of possible PH
(Table 1). Eighty eight percent were women, Caucasians accounting (Fig. 1). After further investigations, documented causes for secondary
for 99.2% of the cohort. The mean age (SD) at SLE diagnosis was 34 PH were found in 11 of them: severe pulmonary obstructive disease
(15) years. The mean time of follow up to the time of enrolment in (n=2), cardiomyopathy or valvulopathy (n=8) and shrinking lung
the screening program was 10.7 (8) years. Previous SLE manifestations syndrome (n=1).
and treatments received are shown in Table 1. After excluding causes for secondary PH, 6 patients remained
with unexplained possible PH. Three of them, all asymptomatic
3.2. Prevalence of PH from the respiratory point of view, had measured TJVs b 3 m/s
in both echocardiograms. A reduction in the PAP values between
The estimated PAP (SD) obtained in the first echocardiography the first and the second echocardiogram was observed in all three
was 32.4 (7.4) mm Hg. One hundred twenty four patients (50%) had cases (43 and 42 mm Hg, 43 and 40 mm Hg and 46 and 40 mm Hg,
a PAP ≥ 30 mm Hg and 33 patients (13.5%) had a PAP ≥ 40 mm Hg. respectively). These patients were kept under clinical observation,
One hundred eighty nine patients had a second echocardiogram all remaining free of cardio-respiratory symptoms up to 2012, with
done within a year, with a mean PAP (SD) of 32.5 mm Hg (7.5). The subsequent echocardiograms showing further decreases in PAP and
mean between both echocardiograms was non-significant (mean TJV values.
difference 0.12, 95% CI − 1.1–0.9, p = 0.8). Cardiac catheterization was performed in the three patients with
Two patients died before performing the second echocardiogram, in- repeated PAP ≥ 40 mm Hg and TJV ≥3 m/s. The resting mean PAP was
dicated as per protocol. The first patient was a 56 year-old woman, with 20 mm Hg in two patients. In the third patient, a 63 year-old woman
SLE and antiphospholipid syndrome. The first echocardiogram showed a with arterial hypertension and evidence of mild diastolic dysfunction
severe mitral valve regurgitation with a PAP of 70 mm Hg. She died sud- in the echocardiograms, the cardiac catheterization found a mean PAP
denly shortly after discharge. No necropsic study was performed. The of 39 mm Hg, with increased pulmonary capillary pressures and signs
second patient was a 74 year-old man, with longstanding end-stage of left ventricular diastolic dysfunction. Accordingly, a diagnosis of PH
renal disease on hemodialysis, ischemic myocardiopathy and moderate secondary to left ventricular dysfunction was made.
mitral regurgitation. The screening echocardiogram showed a PAP of In summary, our screening program detected 12 patients with PH,
49 mm Hg. The patient died within the following year after several secondary in all cases, with a resulting prevalence of 5%. No cases of
episodes of pulmonary edema. SLE-associated PAH were found.
 G. Ruiz-Irastorza et al. / Autoimmunity Reviews 12 (2013) 410–415 413

Study group 3.4. Clinical associations of estimated PAP

n = 245

Three variables showed an association with the PAP values in the

PAP < 40 mmHg in the PAP ≥ 40 mmHg in the first echocardiogram: age at SLE diagnosis (p = 0.0001), age at the
first echocardiogram first echocardiogram time of the echocardiogram (p = 0.0001) and SDI (p = 0.006). In the
n = 212 n = 33 multivariate model, only the age at the time of the echocardiogram
remained independently significant (regression coefficient 0.14, p =
Died before 0.0001), with SDI showing a borderline association (regression coeffi-
Second echocardiogram
performed
second cient 0.49, p = 0.08).
echocardiogram
n = 31 In the 189 patients with two echocardiograms, the PAP increased by
n=2
a mean (SD) 0.12 (6.9) mm Hg between the first and the second echo-
cardiogram. In the same period, the SLEDAI score decreased by a
PAP < 40 mmHg in the PAP ≥ 40 mmHg in the mean (SD) 0.9 (3.8). No relation was seen between both variables by
second echocardiogram second echocardiogram linear regression (p= 0.8). Likewise, no association was either found
n = 14 n = 17 in the subgroup with an estimated PAP ≥40 mm Hg in the first echo-
cardiogram (p= 0.38).

Possible PAH Secondary PH 3.5. Clinical associations of PH

n=6 n = 11
Four variables were associated with PH: age at SLE diagnosis
(OR 1.07, 95% CI 1.02–1.11), time of follow up (OR 1.08, 95% CI 1.01–
TJV < 3 TJV ≥ 3 1.15), age at the time of the first echocardiogram (OR 1.10, 95%
n=3 n=3 CI 1.06–1.17) and arterial hypertension (OR 3.68, 95% CI 1.07–12.60).
In the multivariant logistic regression model, only the age at the time
Clinical follow-up Right heart catheterization
of the first echocardiogram showed an independent association with
PH.
Repeated n=3
echocardiograms showing
decreasing PAP 4. Discussion
Mean PAP ≥ 25 mmHg
Mean PAP < 25 mmHg
Increased wedge PH can complicate the course of SLE. Chronic cardiopulmonary
No PAH pressure conditions can increase PAP, and PAH, i.e., without concomitant cardiac
n=2 Secondary PH or respiratory underlying disease, can also happen in SLE [20].
n=1 The availability of echocardiography has facilitated the screening
of PH, being a non-invasive, no harming and reproducible technique.
Fig. 1. Results of the screening program for pulmonary hypertension. PAP: Pulmonary However, the values obtained by echocardiogram in individual
systolic pressure value. PH: Pulmonary hypertension. PAH: Pulmonary arterial hyper-
patients can overestimate the real PAP values [21]. On the other hand,
tension. TJV: Tricuspid jet velocity.
mild cases of PH can be overlooked [3]. The definitive diagnostic test
for PH is right cardiac catheterization, although the diagnosis of second-
ary PH can be made in patients with elevated PAP values by echocardi-
3.3. Sensitivity, specificity and predictive values ography and a likely underlying cause detected by non-invasive
methods [3]. On the other hand, direct measurement of PAP values
The sensitivity, specificity and predictive values for the different and pulmonary arterial wedge pressures by right heart catheterization
screening cutoffs (one single PAP ≥ 30 mm Hg, one single PAP ≥ is required for the diagnosis of PAH [3].
40 mm Hg and two consecutive PAPs ≥ 40 mm Hg) are shown in Due to this screening limitations, the actual prevalence of PH in SLE is
Table 2. The sensitivity and negative predictive value were 100% for not known. Table 3 shows the prevalence of PH reported in several lupus
all the screening procedures. However, major differences in specifici- cohorts. The diagnosis was made exclusively by echocardiography in
ty and positive predictive values were seen, especially with regard to most studies, with a cutoff PAP value of 30 mm Hg in a single echocardio-
a cutoff level of 30 mm Hg, which showed a specificity of 52% and a gram used in many of them. This approach could overestimate the prev-
positive predictive value of 10%, as compared with 97% and 70%, alence of PH, without discriminating between PAH and secondary PH.
respectively, for two consecutive PAP values ≥ 40 mm Hg. A recent Argentinean necropsic study found plexiform lesions, highly
suggestive of PAH, in 4.4% of 90 patients [28], however, being this a
post-mortem study a selection bias is likely.
A recent systematic review of 23 studies (1 prospective cohort
Table 2 study, 10 retrospective cohort studies and 12 case series or case
Sensitivity, specificity, positive and negative predictive values for the different screening reports) identified several factors associated with decreased survival
definitions of pulmonary hypertension.
in SLE patients with PH: elevated PAP, Raynaud's phenomenon,
S SP PPV NPV thrombosis, antiphospholipid antibodies, pregnancy and infection
PAP >30 100 52 10 100 [32]. The presence of plexiform lesions or pulmonary vasculitis was
PAP >40 100 91 38 100 frequent in patients who eventually died. On the other hand, lupus ac-
PAP >40 × 2a 100 97 70 100 tivity, lupus nephritis and central nervous system involvement had
S: sensitivity. not prognostic implications. These conclusions were limited by the
SP: specificity. low quality of the studies and the heterogeneity of PH definitions [32].
PPV: positive predictive value. Some authors advocate that inflammation plays an important role in
PPV: positive predictive value.
NPV: negative predictive value.
SLE-associated PAH. Indeed, response to immunosuppressive therapy
PAP: systolic pulmonary arterial pressure estimated by echocardiography. has been seen in small retrospective series [33,34]. This potential
a
Two consecutive measurements over 40 mm Hg within 6 months to 1 year. reversibility of PAH could partially explain the better prognosis of PAH
414 G. Ruiz-Irastorza et al. / Autoimmunity Reviews 12 (2013) 410–415

Table 3
Prevalence of pulmonary hypertension in studies of lupus patients.

Author/year No of patients Diagnosis Type of study Symptoms Prevalence of PH

(ref)

Perez et al. 1981 [22] 43 Catheterization Retrospective Symptomatic 9%

Baudi et al. 1985 [23] 100 Symptoms + chest X-ray + echocardiogram Prospective Asymptomatic 9%
Simonson et al.1989 [9] 36 Echocardiogram (PAP > 30 mm Hg) Prospective Asymptomatic 14%
Asherson et al. 1990 [11] ~500 Catheterization Prospective Symptomatic ~5%
Winslow et al. 1995 [16] 28 Echocardiogram (PAP > 30 mm Hg) Prospective Asymptomatic 14%/43%a
Li et al.1999 [6] 419 Echocardiogram (PAP > 30 mm Hg)/Autopsy Retrospective Symptomatic 4.2%
Ling-Te Pan et al. 2000 [24] 786 Echocardiogram (PAP > 30 mm Hg) Retrospective Symptomatic 6%
Tanaka et al.2002 [25] 194 Echocardiogram (PAP > 40 mm Hg) Retrospective Symptomatic 6.2%
Johnson et al.2004 [26] 120 Echocardiogram (PAP > 40 mm Hg) Retrospective Symptomatic 14%
Cefle et al. 2009 [15] 104 Echocardiogram (PAP > 30 mm Hg) Retrospective Symptomatic 1.8%
Prabu et al. 2009 [27] 288 Echocardiogram (PAP > 30 mm Hg) Prospective Asymptomatic 4.2%
Quadrelli et al. 2009 [28] 90 Autopsy Retrospective Asymptomatic 4.4%
Foïse et al. 2010 [29] 93 Echocardiogram (PAP > 35 mm Hg) Retrospective NA 13%
Kamel et al. 2011 [30] 74 Echocardiogram (PAP > 30 mm Hg) Prospective Asymptomatic 10.8%
Bourre-Tessier et al. 2011 [31] 217 Echocardiogram (PAP > 40 mm Hg) Prospective Asymptomatic 10.1%

PH: pulmonary hypertension.

PAP: systolic pulmonary arterial pressure estimated by echocardiography.
a
14% in the initial study, 43% 5 years later, after repeating the screening.

in lupus, with cumulative survivals over 75% at 5 years, compared
with systemic sclerosis [33,35]. Our results did not show a relationship
between the echocardiographic PAP and the SLEDAI score, however,
this finding could be limited by the fact that most patients had low
activity at the time of the echocardiogram.
This is the first study with a structured diagnostic protocol for PH in
lupus patients, including a universal screening program using echocar-
diography, a specific search for cardiopulmonary causes of PH in those
with repeatedly high PAP values and a right heart catheterization in
patients with a high suspicion of PAH. A cutoff point of 40 mm Hg
was set for PAP values suggestive of PH [2]. Moreover, at least two
consecutive measurements ≥ 40 mm Hg were required for the diagno-
sis of possible PH.
The main finding of our study was the lack of confirmed cases of
PAH. Previous to this study, 4 patients with symptomatic PAH diag-
nosed by catheterization had been attended in our lupus cohort, all
dying before 2004. No new cases have been identified up to 2012.
Thus, despite the intrinsic limitations of a cross-sectional study, we
can conclude that PAP is rare in SLE and unlikely to be found in
asymptomatic patients. On the other hand, 12 patients with PH sec-
ondary to cardiac or pulmonary disease were diagnosed. In 5 addi-
tional patients, suspected PH was excluded after thorough medical
evaluation, including repeated echocardiograms, close clinical
follow-up and, eventually, right heart catheterization.
The resulting frequencies for the different PAP cutoffs were 50% for
one single PAP≥30 mm Hg, 13.5% for one single PAP ≥40 mm Hg, 6%
for possible PH (defined as two consecutive PAP≥40 mm Hg), 5% for
confirmed PH (secondary in all cases ) and 0% for PAH. These data remark
the importance of choosing an adequate diagnostic strategy in order to
estimate the real prevalence of PH, both secondary and SLE-related PAH.
In keeping with our results, a single echocardiogram with a PAP≥
30 mm Hg seems completely inaccurate, not only as a diagnostic test,
but also as the single screening procedure to detect PH in asymptomatic
lupus patients. Recent guidelines recommended that the cutoff be set at
40 mm Hg [2]. Indeed, our results clearly show that two consecutive
PAP values≥ 40 mm Hg are a good screening procedure to initiate the
formal evaluation of PH, with positive and negative predictive values
of 70% and 100%, respectively. The presence of a high regurgitation
peak velocity and additional echocardiographic features suggestive of
PH should be also taken into account to decide the following diagnostic
strategy [3].
This study has several limitations. Patients were heterogeneous in
terms of age, disease duration, damage and comorbidities. Most of
them were in clinical remission, which could have biased the analysis
of the association between lupus activity and PAP. The lack of cases
with PAH precluded the analysis of the potential predictors of this
condition. As expected, age and hypertension were among the vari-
ables related with secondary PH. The gold standard used for the cal-
culation of sensitivity, specificity and predictive values was the final
diagnosis after the study rather than the PAP measured by right
heart catheterization, due to obvious ethical and practical limitations.
The resulting sensitivity was therefore 100% for all cutoff values,
given that no patients with a PAP b 40 mm Hg were further studied.
No patients developed symptomatic PH during the follow up after
completing the study, a fact that supports the validity of the final di-
agnosis. However, the presence of patients with mild PH who are not
yet symptomatic or even the response of some cases to immunosup-
pressive treatment cannot be excluded.
Given the low prevalence of PH, routine screening in asymptomatic
lupus patients is not recommended. Suggestive clinical manifestations
should prompt the clinician to start the diagnostic process with a trans-
thoracic echocardiogram. New biomarkers of myocardial dysfunction
such as natriuretic peptides may aid the clinician in the near future.
However, despite some reports of their utility in scleroderma-related
PAH, the potential interference of inflammation in their synthesis
makes their use at this time strictly experimental [36,37].
Take-home messages
• PH, and particularly PAH, is not a major clinical problem in patients
with SLE.
• Screening echocardiograms of asymptomatic lupus patients with-
out a clinical suspicion of PH is not recommended.
• Two consecutive PAP values ≥ 40 mm Hg estimated by echocardio-
gram are the best initial procedure to decide further testing for the
diagnosis of PH.
Contributorship statement
Conception and design: GR-I, MG, M-VE, CA.
Analysis and interpretation of data: GR-I, MG, IV.
Drafting the article or revising it critically for important intellectual
content: All authors.
Final approval of the version to be published: All authors.
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